Search Results (181)

Background/Objectives: Ovarian follicular cysts (OFCs) in dairy cows represent a significant cause of infertility and share striking similarities with polycystic ovary syndrome (PCOS) in women. This study aimed to elucidate the molecular mechanisms underlying OFCs and their relevance to PCOS by profiling differentially expressed (DE) microRNAs (miRNAs) and constructing integrative RNA interaction networks. Methods: Expression analysis of 84 bovine miRNAs was conducted in antral follicular fluid from normal and cystic follicles using miScript PCR arrays. Bioinformatic tools including miRBase, miRNet, and STRING were employed to predict miRNA targets, construct protein–protein interaction networks, and perform gene ontology and KEGG pathway enrichment. Network analyses integrated miRNAs with coding (mRNAs) and non-coding RNAs (circRNAs, lncRNAs, snRNAs). Results: Seventeen miRNAs were significantly dysregulated in OFCs, including bta-miR-18a, bta-miR-30e-5p, and bta-miR-15b-5p, which were associated with follicular arrest, insulin resistance, and impaired steroidogenesis. Upregulated miRNAs such as bta-miR-132 and bta-miR-145 correlated with inflammation, oxidative stress, and intrafollicular androgen excess. Key regulatory lncRNAs such as Nuclear Enriched Abundant Transcript 1 (NEAT1), Potassium Voltage-Gated Channel Subfamily Q Member 1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1), Taurine-Upregulated 1 (TUG1), and X Inactive Specific Transcript (XIST), as well as circRNA/pseudogene hubs, were identified, targeting pathways involved in metabolism, inflammation, steroidogenesis, cell cycle, and apoptosis. Conclusions: The observed transcriptomic changes mirror core features of human PCOS, supporting the use of bovine OFCs as a comparative model. These findings provide novel insights into the regulatory RNA networks driving ovarian dysfunction and suggest potential biomarkers and therapeutic targets for reproductive disorders. This network-based approach enhances our understanding of the complex transcriptomic landscape associated with follicular pathologies in both cattle and women. Full article

Background/Objectives: Early diagnosis and oral or, in severe cases, intravenous antibiotics are usually effective for Lyme disease, but some patients have persistent symptoms unresponsive to standards of care, requiring alternative therapies. Disulfiram (DIS), a drug for alcoholism, is under investigation as a potential adjunctive treatment, but its low bioavailability, rapid metabolism, and safety concerns urge the development of improved formulations for clinical translation. Methods: Screening dissolution and permeation studies were investigated for vehicle and excipient selection, following the pharmacopeia perspectives to develop and optimize the low-dose DIS rectal suppository intended for application in post-treatment Lyme disease syndrome (PTLDS). Further characterizations were carried out by differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy. Results: Cyclodextrin (CD) encapsulation was investigated to improve the aqueous solubility of the hydrophobic drug. The dissolution of DIS from fatty base suppository was very slow; it was remarkably improved by the molecular encapsulation of the drug with CDs. The dissolution of DIS from a water-soluble base was more favorable, but incomplete. In the polyethylene glycol (PEG) based suppositories, the addition of CDs already in a physical mixture ensured the dissolution of the drug. The presented drug delivery system relates to a novel preparation for rectal administration comprising a low-dose disulfiram with improved solubility and permeability by the PEG and hydroxypropyl-β-cyclodextrin (HPBCD) synergistic matrix. Conclusions: The rectal dosage form containing the drug and CD in the physical mixture is advantageous, avoiding the hepatic first-pass effect, minimizing dose-limiting toxicity, simplifying production, and fasting the availability of the repositioned drug. Full article

The Mediterranean diet (MD) is one of the healthiest diets, high in fiber, antioxidants, and unsaturated fats. MD improves lipid profiles, reduces inflammation, controls blood pressure, decreases insulin resistance, and enhances the sensitivity to this hormone, lowering the risks of Metabolic syndrome (MS). MS is characterized by central obesity, hypertension, insulin resistance, and dyslipidemia, increasing the risk of cardiovascular disease and type II diabetes. The objective of this study was to know the effectiveness of the MD versus other treatments in patients with MS. A systematic search across multiple databases, Medline, Embase, Web of Science, Scopus, Google Scholar, and Cinahl, was conducted using keywords such as “Mediterranean diet”, “Mediterranean food”, “eat mediterranean”, “Metabolic syndrome”, and “x syndrome”. A total of 12 studies met the inclusion criteria. Mediterranean diet at different doses versus other diets or other treatments showed significant improvements in clinical parameters, including BMI (mean difference of −0.83 95% CI: −0.93 to −0.74; p < 0.00001),waist circumference (mean difference = −1.81, CI = −2.63 to −0.99, p < 0.00001) triglycerides (mean difference = −22.38, CI = −32.86 to −11.90, p < 0.00001), Glucose (mean difference = −4.28, CI = −7.64 to −0.93, p = 0.005) and, HOMA IR (mean difference = −0.72, CI = −0.78 to −0.65, p < 0.00001), and Insulin resistance (mean difference = −2.98, CI = −3.27 to −2.69, p < 0.00001), all of which improved, Although there were more outcomes, these are the most important changes for patients with metabolic syndrome. MD improves metabolic and cardiovascular health, but study heterogeneity limits the results’ generalizability. Because of that, further research is needed to standardize approaches and explore their mechanisms. MD should be part of an optimized strategy that includes education and physical activity. The strength of the evidence was very low according to the GRADE approach. Further research is needed to support the efficacy of the Mediterranean diet in patients with MS. Full article

Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS/MAPK pathway dysregulation on bone health remains poorly understood. Objectives: The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients. Methods: In this cross-sectional, case-control study, we analyzed 28 children (20 males) with a molecular diagnosis of NS and 35 healthy subjects (21 males), matched by age and sex. We assessed markers of bone metabolism and bone turnover (calcium, phosphate, PTH, 25(OH)-vitamin D, osteocalcin, procollagen I N-propeptide-P1NP, bone alkaline phosphatase-BALP, C-telopeptides of type I collagen-CTX) and bone remodeling (RANKL, OPG, and sclerostin). Bone mineralization was measured at the lumbar spine (L2–L4) using dual-energy X-ray absorptiometry (DEXA). Results: Serum CTX levels were significantly higher in NS patients compared to controls (1.8 ± 0.7 vs. 1.3 ± 0.5 ng/mL, p = 0.0004). RANKL levels were higher in NS patients, although the difference did not reach statistical significance. No significant differences were found for OPG, sclerostin, or other markers of bone metabolism between patients and controls. Conclusions: Children with NS exhibit increased bone resorption, as indicated by elevated CTX levels, suggesting a potential imbalance in bone remodeling processes. Further studies are warranted to better define the impact of RAS/MAPK pathway dysregulation on bone health in this population. Full article

The Fragile X Mental Retardation 1 (FMR1) gene is well-known for its role in Fragile X syndrome, a neurodevelopmental disorder, but emerging evidence suggests its involvement in regulating cellular metabolism, with implications for cancer biology. FMR1 encodes the Fragile X mental retardation protein (FMRP), an RNA-binding protein that controls various cellular processes, including translation, synaptic plasticity, and RNA metabolism. Recent studies have uncovered novel links between FMR1, metabolic regulation, and tumorigenesis. This review discusses the role of FMR1 in cellular metabolism and its potential involvement in cancer, focusing on glycolysis, mitochondrial metabolism, lipid metabolism, immune cell metabolism, and tumor immune evasion, and as a potential target to enhance immunotherapy, and highlights future research directions to elucidate its mechanistic roles in cancer. Full article

The cerebellar peduncles (CPs) contain essential pathways connecting the cerebellum and other regions of the central nervous system, yet their role is often overlooked in daily medical practice. Individuals with the FMR1 premutation are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. The major clinical and radiological signs of FXTAS are cerebellar gait ataxia, intention tremor, and T2-weighted MRI hyperintensity of the middle cerebellar peduncle (MCP sign). Over the years, metabolic and structural abnormalities have also been described in the CPs of FMR1 premutation carriers, with some being associated with CGG repeat length and FMR1 mRNA levels. Evidence seems to associate the clinical disfunction observed in FXTAS with MCP abnormalities. However, other tracts within the different CPs may also contribute to the symptoms observed in FXTAS. By integrating imaging and pathological data, this review looks to enhance the understanding of the functional anatomy of the CPs and their involvement in different pathological entities, with special interest in premutation carriers and FXTAS. This review, therefore, aims to provide accessible knowledge on the subject of the CPs and their functional anatomy through detailed diagrams, offering a clearer understanding of their role in FMR1 premutation. Full article

Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders. Full article

Metabolic bone disease (MBD) is a known complication of short bowel syndrome (SBS), with a high prevalence in both pediatric and adult populations. MBD includes various conditions that disrupt skeletal homeostasis, such as rickets, osteomalacia, and osteoporosis. The pathogenesis of MBD is multifactorial, regardless of the underlying cause of SBS. When MBD is suspected, it is important to conduct laboratory evaluations to guide proper diagnosis and treatment. Dual-energy X-ray absorptiometry (DXA) is the preferred imaging modality for assessing MBD in routine clinical care. Early and accurate diagnosis and treatment of MBD in pediatric patients with SBS are essential to support growth and development and prevent fractures and metabolic complications. Using the best evidence available, this article aims to review the pathophysiology, diagnosis, and current management of MBD in pediatric patients with SBS. Full article

RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation into new candidate genes encoding other elements of the complex could reveal further details regarding APOBEC-mediated mRNA editing. Menkes disease is a recessive X-chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from a macular mouse model of Menkes disease withs T>C mutation. Around 35% of the mutated C nucleotide (nt) was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field. Full article

For many genetic disorders, there are no specific metabolic biomarkers nor analytical methods suitable for newborn population screening, even where highly effective preemptive treatments are available. The direct measurement of signature peptides as a surrogate marker for the protein in dried blood spots (DBSs) has been shown to successfully identify patients with Wilson Disease (WD) and three life-threatening inborn errors of immunity, X-linked agammaglobulinemia (XLA), Wiskott–Aldrich syndrome (WAS), and adenosine deaminase deficiency (ADAD). A novel proteomic-based multiplex assay to detect these four conditions from DBS using high-throughput LC-MS/MS was developed and validated. The clinical validation results showed that the assay can accurately identify patients of targeted disorders from controls. Additionally, 30,024 newborn DBS samples from the Washington State Department of Health Newborn Screening Laboratory have been screened from 2022 to 2024. One true presumptive positive case of WD was found along with three false positive cases. Five false positives for WAS were detected, but all of them were premature and/or low-birth-weight babies and four of them had insufficient DNA for confirmation. The pilot study demonstrates the feasibility and effectiveness of utilizing this multiplexed proteomic assay for newborn screening. Full article

Background/Objective: Metabolic syndrome (MetS) is characterized by abdominal obesity, increased blood pressure (BP), fasting blood glucose (FBG) and triglyceride levels, and reduced high-density lipoprotein (HDL) levels. This study aims to investigate the efficacy of the Wharton’s jelly mesenchymal stem cells (WJMSCs)-derived small extracellular vesicles’ (sEVs) preparations in managing MetS. Method: Twenty-four rats were fed with a high-fat and high-fructose diet to induce MetS for 16 weeks and randomized into three groups (n = 8/group): a MetS Control group treated with normal saline, MetS Low Dose (LD) group treated with a LD of sEVs preparations (3 × 10⁹ particle/rat), and MetS High Dose (HD) group treated with a HD of sEVs preparations (9 × 10⁹ particles/rat). The Control Non-Disease (ND) group was given a standard rat diet and autoclaved tap water with normal saline as treatment. Treatments were given via intravenous injection every three weeks for twelve weeks. Rats were assessed every six weeks for physical measurements, FBG, lipid profiles, CRP, leptin, adiponectin, and BP. Necropsy evaluation was performed on the lungs, liver, spleen, and kidney. Results: Significant reductions in FBG, triglycerides, BP, and increased HDL levels were observed in the treated groups compared to the control group. However, significant abdominal circumference (AC) improvement was not observed in the treated groups. Non-significant associations were found between fasting CRP, leptin, and adiponectin levels with MetS rats after treatment. In addition, sEVs preparations improved inflammation and hemorrhage in the lung and mineralisation in the renal of the treated group. Conclusions: Human fetal WJMSCs-derived sEVs preparations improve all the clusters of MetS in rats except AC and could be further explored as a treatment for MetS. Full article

Background: Fructose (50% of sucrose/sugar) is one component of free-sugars and is metabolized to uric acid, which is a known risk factor for gout and metabolic syndrome. Pacific peoples in New Zealand experience a higher prevalence of gout, type 2 diabetes, and overweight/obesity than other ethnic groups. Interestingly, despite having a similar body mass index (BMI), they tend to have a higher proportion of appendicular skeletal muscle mass (ASMM) and less fat than other ethnic groups. Given this context, this study aimed to evaluate the associations between serum uric acid (SUA), free-sugar intake, and ASMM. Methods: In a nested sub-study from the Pacific Islands Families birth-cohort study, 101 boys and 99 girls (all aged 14 and 15 years) self-reported how often they had consumed foods containing sugar in the past month. Anthropometry, body fatness, and ASMM by dual-energy X-ray absorptiometry and metabolic risk factors, including SUA were measured. Results: Overall, 43% of girls and 57% of boys consumed ‘sugary drinks’ twice or more a day. When analyzed by group, ASMM was positively related to SUA for both boys and girls (r = 0.593, p < 0.0001). The effect of the intake of ‘sugary drinks’ on SUA (r = 0.176, p = 0.013) was reduced when ASMM was considered in the relationships. Conclusions: This study shows high SUA levels in Pacific adolescents, with a positive association between ASMM and SUA in both genders. Sugary drink intake was positively associated with SUA in both boys and girls. High ASMM in Pacific people and an increased risk for raised SUA make it important to work with Pacific communities to reduce added sugar intake and adopt integrated, family-based, culturally centered, and life-course approaches to prevent chronic diseases, including gout. Full article

Background: Lesch–Nyhan syndrome (LNS) is a rare X-linked recessive metabolic disorder caused by mutations in the HPRT1 gene, resulting in hypoxanthine–guanine phosphoribosyltransferase (HPRT) deficiency. Early diagnosis is critical for optimizing management and improving outcomes. This study presents a case series of three Taiwanese patients diagnosed at a single medical center. Methods: Exome sequencing and biochemical testing were used to confirm the diagnoses. Early clinical manifestations, including hyperuricemia, hypotonia, and developmental delay, were documented during the initial stages of the disease. Results: All three patients had hyperuricemia, hypotonia, spasticity, and motor developmental delay. Pathogenic variants in the HPRT1 gene were identified in two patients, while the third was confirmed by biochemical testing. Two patients had orange-colored crystalline deposits in their diapers, indicative of hyperuricosuria. Self-injurious behavior had not yet developed in two patients due to their young age. Conclusions: Early clinical features such as hyperuricemia, hypotonia, and motor delay may suggest LNS in infancy. Molecular genetic testing, particularly whole exome sequencing, can facilitate an early diagnosis before specific manifestations occur, enabling timely interventions and improving patient outcomes. Full article

Polyphenols have antioxidant and anti-inflammatory properties and maintain the immune system in balance; therefore, the aim of the study was to investigate the effect of polyphenols present in pomegranate peel extract on the spleens of rats with metabolic syndrome. The study objects were adult male Zucker Diabetic Fatty (ZDF-Leprfa/Crl, fa/fa) rats. The rats were divided into a control group (MetS) consisting of rats with metabolic syndrome and four study groups consisting of rats with metabolic syndrome (MetS + 100 mg and MetS + 200 mg) or healthy animals (H + 100 mg and H + 200 mg) receiving polyphenol extract at a dose of 100 mg or 200 mg/kg, respectively. Concentrations of IL-6, NF-κB, NFATc1, Cyt-C, TNFα, MMP-2, ROS/RNS, and MDA were measured; the activities of GPX, SOD, CAT, MMP-2, and MMP-9 were assessed; and the expression of the BAX and BCL-2 genes was evaluated in homogenized spleens. In conclusion, pomegranate extract may lead to an increase in catalase and glutathione peroxidase activity. Additionally, it may have a reducing effect on the ROS/RNS level, leading to a reduction in the activity of SOD in the MetS groups with PPE administration. Moreover, the BCL-2 gene showed lower expression in the MetS + 100 mg group compared to the H + 100 mg group, indicating that the balance between pro- and antiapoptotic factors of the BCL-2 family may be disrupted by the metabolic syndrome promoting the proapoptotic pathway. Full article

Background: Metabolic syndrome refers to the coexistence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia, and hypertension. These conditions are interrelated and share underlying mediators, mechanisms, and pathways. Improvement in dietary habits has been shown to improve metabolic parameters in patients undergoing treatment with different diets. Methods: A systematic search in different databases was realized using the keywords “Metabolic syndrome”, “X syndrome”, “Dash dietary” and “Dash diet”. Finally, six studies were included in this meta-analysis. Results: All articles comparing the DASH diet vs. other diet modalities reported significant differences in favor of the DASH diet on Systolic blood pressure (SBP) (standardized mean difference [SMD] = −8.06, confidence interval [CI] = −9.89 to −7.32, and p < 0.00001), Diastolic blood pressure (SMD = −6.38, CI = −7.62 to −5.14, and p < 0.00001), Cholesterol HDL (SMD = 0.70, CI = 0.53 to 0.88, and p < 0.00001) and Cholesterol LDL (SMD = −1.29, CI = −1.73 to −0.85, and p < 0.00001) scales. Conclusions: The DASH diet has been shown to be beneficial in altered parameters in patients with MS, and the resulting improvements can significantly affect the daily health of these patients. We therefore recommend that professionals who manage these pathologies promote the use of the DASH diet for the management of specific symptoms. Full article